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Pharmacological profile of [i]Ascaris suum[/i] ACR-16, a new homomeric nicotinic acetylcholine receptor widely distributed in [i]Ascaris[/i] tissues
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Control of nematode parasite infections relies largely on anthelminthic drugs, several of which act on nicotinic acetylcholine receptors (nAChRs) and there are concerns about the development of resistance. There is an urgent need for development of new resistance-busting drugs and novel anthelmintic drug targets. We describe the functional expression and pharmacological characterization of the homomeric nAChR, ACR-16, from a nematode parasite.[br/]Using RT-PCR, molecular cloning, and two-electrode voltage-clamp electrophysiology, we localized acr-16 mRNA in Ascaris suum, then cloned and expressed acr-16 cRNA in Xenopus oocytes. Sensitivity of the receptor to cholinergic anthelmintics and a range of nicotinic agonists was then tested.[br/]Amino acid sequence comparison with vertebrate nAChR subunits revealed ACR-16 to be most closely related to α7 receptors, but with some striking distinctions. acr-16 mRNA was recovered from A. suum somatic muscle, pharynx, ovijector, head and intestine. In electrophysiological experiments, we observed that existing cholinergic anthelmintic agonists (morantel, levamisole, methyridine, thenium, bephenium, tribendimidine & pyrantel) did not activate Asu-ACR-16 (except for small currents to oxantel). Other nAChR agonists: nicotine, acetylcholine, cytisine, 3-bromocytisine and epibatidine produced robust current responses which desensitized at a rate that varied with the agonists. Unlike α7, Asu-ACR-16 was insensitive to α-bungarotoxin, and did not respond to genistein or other α7 positive allosteric modulators. Asu-ACR-16 had a lower calcium permeability than α7 receptors.[br/]We suggest that ACR-16 has diverse tissue-dependent functions in nematode parasites and is a suitable drug target for development of novel anthelmintic compounds.
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